Abstract (Parent grant): Cannabis is used by more than half of all people with bipolar disorder (BD), which may increase with continued legalization across the United States. Some but not all of the deleterious cognitive effects of cannabis are likely exaggerated in people with BD, given that the brain's endocannabinoid (ECB) system affects the function of dopaminergic (DA) circuitry, which is thought to be dysregulated in BD. For example, administration of the cannabinoid1 (CB1) receptor agonist delta-9-tetrahydrocannabidiol (THC) - the primary active ingredient in cannabis - increases DA release in the striatum. This effect is especially problematic in BD individuals who have reduced expression of the dopamine transporter (DAT), the mechanism driving homeostatic regulation of DA levels. On the other hand, cannabidiol (CBD) is the other major ingredient of cannabis and does not increase DA levels, so cannabis containing high CBD may not be as deleterious. A better understanding of the consequences of chronic cannabis use on critical cognitive functions and ECB/DA neurochemistry in BD could further the development of treatments for BD and substance use disorders. The proposed use of cross-species measures and parallel studies in both humans and rodents enables a more nuanced understanding of both the neurobiology and clinical applicability of the ECB system in BD. Aim 1 will determine the effects of chronic cannabis use on cognitive functions relevant to BD, in chronic cannabis users and non-users compared to healthy comparison (HC) participants. A battery of cognitive and behavioral tests that measure domains such as arousal, inhibitory control, feedback-based decision making, reward preference, and temporal perception will be administered. Aim 2 will identify the effects of acute exposure to controlled doses of THC and CBD on cognition and determine the resulting levels of endogenous cannabinoids such as anandamide (AEA) and the DA metabolite homovanillic acid (HVA) via lumbar puncture. Infrequent cannabis- using BD and HC participants will be randomized to receive one of 3 preparations of placebo, THC, or THC/CBD and will be tested on the cognitive-behavioral battery. Aim 3 will determine the interactive effects of reduced DAT function (a validated mouse model for BD) and THC/CBD treatment (acute, chronic, and withdrawal states) on cognition, neuropathology, plus ECB, DA receptor, and AEA expression in mice. The rodent behavioral tests have direct translational applicability to the human tests described above. It is hypothesized that BD participants and mice with reduced DAT expression will show interactive and additive effects of chronic cannabis use both on cognition and on ECB and HVA levels, due to complex interactions between the ECB and DA systems. Acute THC exposure may decrease arousal and improve temporal perception in BD and KD mice but impair inhibition and decision making, whereas CBD will not exert as deleterious effects. In addition to shedding new light on the neurobiology of BD and cannabis use disorder, these studies may inform how pharmacological manipulation of the ECB system can become a novel approach for treating BD.